Vascular system defects and neuronal apoptosis in mice lacking Ras GTPase-activating protein

Henkemeyer, Mark; Rossi, Derrick J.; Holmyard, Douglas; Puri, Mira C.; Mbamalu, Geraldine; Harpal, Kendraprasad; Shih, T. Shane; Jacks, Tyler; Pawson, Tony

doi:10.1038/377695a0

Cited by 345 publications

(252 citation statements)

References 42 publications

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“…No di erences in the magnitude of the increase in MAPK activation following EGF stimulation were observed between Nf1+/+ and Nf1+/7 astrocyte cultures after quantitation by scanning densitometry proliferation, we examined mice heterozygous for a mutation in the another rasGAP molecule, p120-GAP. Mice homozygous for a targeted mutation in the Gap gene are embryonic lethal while heterozygotes fail to develop astrocytic tumors (Henkemeyer et al, 1995). We quantitated the number of GFAP-immunoreactive astrocytes in representative regions of the brain and detected no reproducible di erences between wild type and Gap+/7 mice (right CA1 region; Figure 5d).…”

Section: Increased Astrocyte Proliferation Is a Neuro®bromin-speci®c mentioning

confidence: 98%

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Haploinsufficiency for the neurofibromatosis 1 (NF1) tumor suppressor results in increased astrocyte proliferation

et al. 1999

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Individuals a ected with neuro®bromatosis 1 (NF1) harbor increased numbers of GFAP-immunoreactive cerebral astrocytes and develop astrocytomas that can lead to blindness and death. Mice heterozygous for a targeted Nf1 mutation (Nf1+/7) were employed as a model for the human disease to evaluate the hypothesis that reduced NF1 protein (neuro®bromin) expression may confer a growth advantage for astrocytes, such that inactivation of only one NF1 allele is su cient for abnormal astrocyte proliferation. Here, we report that Nf1+/7 mice have increased numbers of cerebral astrocytes and increased astrocyte proliferation compared to wild-type littermates. Intriguingly, primary Nf1+/7 astrocyte cultures failed to demonstrate a cell-autonomous growth advantage unless they were cocultured with C17 neuronal cells. This C17 neuronal cellinduced Nf1+/7 increase in proliferation was blocked by MEK inhibition (PD98059), suggesting a p21-rasdependent e ect. Furthermore, mice heterozygous for a targeted mutation in another GAP molecule, p120-GAP, demonstrated no increases in cerebral astrocyte number. These ®ndings suggest that reduced NF1 expression results in a cell context-dependent increase in astrocyte proliferation that may be su cient for the development of astrocytic growth abnormalities in patients with NF1.

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Section: Increased Astrocyte Proliferation Is a Neuro®bromin-speci®c mentioning

confidence: 98%

“…Gap+/7 mice have been previously described (Henkemeyer et al, 1995). Both are maintained as continuous colonies at Washington University.…”

Section: Primary Astrocyte Culturesmentioning

confidence: 99%

Haploinsufficiency for the neurofibromatosis 1 (NF1) tumor suppressor results in increased astrocyte proliferation

et al. 1999

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“…In the case of both p120 Ras GAP and NF1, a considerable body of indirect evidence suggests that these molecules may play roles in controlling non-Raf/MAPK pathways activated by Ras which may be essential for such neoplastic properties as invasiveness . p120 GAP-or NF1-de®cient mice have been described and both lead to death during embryogenesis (Henkenmeyer et al, 1995;Bollag et al, 1996). The analysis of whether Ras transforming potential is impaired in ®broblasts derived from the embryos of these animals will provide further assessment of whether Ras GAPs are important e ectors of Ras transformation and may identify the signaling pathways that they regulate.…”

Section: Ras Mediates Its Actions Through Interaction With Multiple Ementioning

confidence: 99%

Increasing complexity of Ras signaling

et al. 1998

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The initial discovery that ras genes endowed retroviruses with potent carcinogenic properties and the subsequent determination that mutated ras genes were present in a wide variety of human cancers, prompted a strong suspicion that the growth-promoting actions of mutated Ras proteins contribute to their aberrant regulation of growth stimulatory signaling pathways. In 1993, a remarkable convergence of experimental observations from genetic analyses of Drosophila, S. cerevisiae and C. elegans as well as biochemical and biological studies in mammalian cells came together to de®ne a clear role for Ras in signal transduction. What emerged was an elegant linear signaling pathway where Ras functions as a relay switch that is positioned downstream of cell surface receptor tyrosine kinases and upstream of a cytoplasmic cascade of kinases that included the mitogen-activated protein kinases (MAPKs). Activated MAPKs in turn regulated the activities of nuclear transcription factors. Thus, a signaling cascade where every component between the cell surface and the nucleus was de®ned and conserved in worms,¯ies and man. This was a remarkable achievement in our e orts to appreciate how the aberrant function of Ras proteins may contribute to the malignant growth properties of the cancer cell. However, the identi®cation of this pathway has proven to be just the beginning, rather than the culmination, of our understanding of Ras in signal transduction. Instead, we now appreciate that this simple linear pathway represents but a minor component of a very complex signaling circuitry. Ras signaling has emerged to involve a complex array of signaling pathways, where cross-talk, feedback loops, branch points and multi-component signaling complexes are recurring themes. The simplest concept of a signaling cascade, where each component simply relays the same message to the next, is clearly not the case. In this review, we summarize our current understanding of Ras signal transduction with an emphasis on new complexities associated with the recognition and/or activation of cellular e ectors, and the diverse array of signaling pathways mediated by interaction between Ras and Ras-subfamily proteins with multiple e ectors.

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“…Furthermore, it was shown that mice with a null mutation of either the RasGAP or huntingtin gene exhibit increased neuronal apoptosis. 41 Finally, it is well established that PSD95 (postsynaptic density protein 95) interacts with Huntingtin. 33 PSD95 binds to certain glutamate receptors, that is NMDA-or kainate receptors, and to cytoplasmic signaling proteins such as one member of the above-mentioned RasGAP, SynGAP.…”

Section: Structural Aspects and Protein Interactors Of Human Exon 1 Hmentioning

confidence: 99%

Mutant huntingtin can paradoxically protect neurons from death

Züchner

Brundin

2007

Cell Death Differ

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Huntington's disease (HD) is a progressive neurodegenerative disorder caused by a mutation in the gene huntingtin and characterized by motor, cognitive and psychiatric symptoms. Huntingtin contains a CAG repeat in exon 1. An expansion of this CAG repeat above 35 results in misfolding of Huntingtin, giving rise to protein aggregates and neuronal cell death. There are several transgenic HD mouse models that reproduce most of the features of the human disorder, for example protein inclusions, some neurodegeneration as well as motor and cognitive symptoms. At the same time, a subgroup of the HD transgenic mouse models exhibit dramatically reduced susceptibility to excitotoxicity. The mechanism behind this is unknown. Here, we review the literature regarding this phenomenon, attempt to explain what protein domains are crucial for this phenomenon and point toward a putative mechanism. We suggest, that the C-terminal domain of exon 1 Huntingtin, namely the proline rich domain, is responsible for mediating a neuroprotective effect against excitotoxicity. Furthermore, we point out the possible importance of this mechanism for future therapies in neurological disorders that have been suggested to be associated with excitotoxicity, for example Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis.

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Vascular system defects and neuronal apoptosis in mice lacking Ras GTPase-activating protein

Cited by 345 publications

References 42 publications

Haploinsufficiency for the neurofibromatosis 1 (NF1) tumor suppressor results in increased astrocyte proliferation

Haploinsufficiency for the neurofibromatosis 1 (NF1) tumor suppressor results in increased astrocyte proliferation

Increasing complexity of Ras signaling

Mutant huntingtin can paradoxically protect neurons from death

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